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Min SW, Chen X, Tracy TE, Li Y, Zhou Y, Wang C, Shirakawa K, Minami SS, Defensor E, Mok SA, Sohn PD, Schilling B, Cong X, Ellerby L, Gibson BW, Johnson J, Krogan N, Shamloo M, Gestwicki J, Masliah E, Verdin E, Gan L. Critical role of acetylation in tau-mediated neurodegeneration and cognitive deficits. Nat Med. 2015 Oct;21(10):1154-62. Epub 2015 Sep 21 PubMed.
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University of Edinburgh
Large amounts of evidence support the idea that abnormal levels of soluble tau are toxic and contribute to neurodegeneration in tauopathies. One of the key questions to move toward therapeutic development is, which types of tau are toxic? This paper points to tau acetylated at lysine 174 as one of the toxic species.
In a comprehensive set of experiments ranging from postmortem AD brain to cultured neurons and two mouse models of tauopathy, the authors demonstrate that increases in levels of this species are associated with toxicity and decreases are beneficial. This indicates that targeting tau acetylation may have therapeutic potential.
While the authors make a strong case for this acetylation being toxic, it is likely that there is more than one toxic species of tau. Indeed, similar effects on reducing pathology and improving cognition have been seen in mice when targeting different phospho-epitopes of tau (Sigurdsson, 2014) and by targeting tau oligomers (Castillo-Carranza et al., 2014). While acetylation, phosphorylation, and oligomerization are not mutually exclusive events, it may take multiple approaches to effectively prevent tau toxicity in humans.
References:
Sigurdsson EM. Tau immunotherapy and imaging. Neurodegener Dis. 2014;13(2-3):103-6. Epub 2013 Sep 11 PubMed.
Castillo-Carranza DL, Sengupta U, Guerrero-Muñoz MJ, Lasagna-Reeves CA, Gerson JE, Singh G, Estes DM, Barrett AD, Dineley KT, Jackson GR, Kayed R. Passive immunization with Tau oligomer monoclonal antibody reverses tauopathy phenotypes without affecting hyperphosphorylated neurofibrillary tangles. J Neurosci. 2014 Mar 19;34(12):4260-72. PubMed.
View all comments by Tara Spires-JonesRIKEN Center for Brain Science
This is a finely designed, beautiful work. A simple concern: Does replacement of the lysine residue by glutamine completely mimic acetylation in structural biology terms? At least biochemically, acetylated lysine and glutamine are quite different.
View all comments by Takaomi SaidoKULeuven
Interesting findings. They illustrate perfectly the major problem that troubles fundamental research into protein tau, in the first instance in AD but evidently in all tauopathies.
As opposed to APP and amyloid, we do know the major physiological function of protein tau: spacing of microtubules to allow transport by motor proteins in both directions. We fail to understand the molecular changes that regulate the dynamics of binding of protein tau to microtubules, and eventually to other proteins and structures, i.e., membranes and/or F-actin.
Free protein tau is a floppy, non-structured protein, and its maximum of 441 amino acids offer a vast array of potential post-translational modifications (PTM). My classic example: If we account for only 15 physiologically relevant phosphorylation sites, the number of different "normal" tau isoforms already reaches 215, or more than 32,000.
Including all other known PTM, and for sure more are still to be discovered, increases that already vast number exponentially. It is evident that all sorts of correlations are observed—some very tight and others more loose. This paper is a fine example of such studies, but only one of many.
Nevertheless, correlation is neither cause nor consequence: the tight correlation between chocolate consumption and Nobel Prize winners, or the arrival of storks and the number of births are of no relevance for the members of these equations.
The reported acetylation is to be regarded in that light. Mice with a specific defect in the enzyme or the residue on tau will shed some more light on what eventually will turn out to be the neuro/synapto-toxic species in ailing brain, in any or all of the many tauopathies.
The excellent data presented in studies like this and others need to be confirmed and followed up tenaciously and stringently to finally answer the primary questions!
View all comments by Fred Van LeuvenMake a Comment
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